Process for separation of 19-nor-Δ4 -androstene-3,17-dione

Abstract

In a process for separating 19-nor-Δ 4 -androstene-3,17-dione from a mixture of steroids which is obtained by the Birch reduction of an alkyl or an aralkyl ether of estrone acetal having the following formula (I), ##SPC1## wherein R is selected from the group consisting of an alkyl group containing 1 to 10 carbon atoms and an aralkyl group containing a side chain of 1 to 5 carbon atoms; X and Y are selected from the group consisting of O-alkyl and S-alkyl groups, respectively, containing 1 to 10 carbon atoms; or the following formula (II), ##SPC2## wherein R is as defined above; Z and W are selected from the group consisting of oxygen atom and sulfur atom; and n represents an integer of from 2 to 10; followed by the hydrolysis of the obtained reduction product of said Birch reduction, the improvement which comprises 1. reacting said mixture of steroids containing 19-nor-Δ 4 -androstene-3,17-dione with a secondary amine to form the C 3 -enamine of 19-nor-Δ 4 -androstene-3,17-dione, 2. extracting the resultant C 3 -enamine of 19-nor-Δ 4 -androstene-3, 17-dione with an aqueous solution of an inorganic acid, and then 3. hydrolyzing the separated C 3 -enamine of 19-nor-Δ 4 -androstene-3,17-dione.

What is claimed as new and intended to be covered by Letters Patent is: 
     
       1. In a process for separating 19-nor-Δ 4  -androstene-3,17-dione from a mixture of steroids which is obtained by the Birch reduction of an alkyl or an aralkyl ether of estrone acetal having the following formula (I), ##SPC6## wherein R is selected from the group consisting of an alkyl group containing 1 to 10 carbon atoms and an aralkyl group containing a side chain of 1 to 5 carbon atoms; X and Y are selected from the group consisting of O-alkyl and S-alkyl groups, respectively, containing 1 to 10 carbon atoms; or the following formula (II): ##SPC7##   wherein R is as defined above; Z and W are selected from the group consisting of oxygen atom and sulfur atom; and n represents an integer of from 2 to 10; followed by the hydrolysis of the obtained reduction product of said Birch reduction, the improvement which comprises:   1. reacting said mixture of steroids containing 19-nor-Δ 4  -androstene-3,17-dione with a secondary amine selected from the group consisting of pyrrolidine piperidine, morpholine and dimethylamine, to form the C 3  -enamine of 19-nor-Δ 4  -androstene-3,17-dione;   2. extracting the resultant C 3  enamine of 19-nor-Δ 4  -androstene-3,17 dione with an aqueous solution of an inorganinc acid selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sodium hydrogen sulfate and sodium hydrogen sulfite, and then;   
     
     
       3. hydrolyzing the separated C 3  -enamine of 19-nor-Δ 4  -androstene-3,17-dione. 
     
     
       2. The process of claim 1, wherein R is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-hexyl, benzyl and phenethyl; X and Y are selected from the group consisting of methoxy, ethoxy, n-butoxy, methylthio, ethylthio and n-butylthio; and --Z--(CH 2 ) n  --W-- is selected from the group consisting of ethylenedioxy, trimethylenedioxy, ethylenedithio and trimethylenedithio. 
     
     
       3. The process of claim 1, wherein the alkyl ether of estrone acetal is estrone methyl ether ethylene acetal. 
     
     
       4. The process of claim 1, wherein the alkyl ether of estrone acetal is estrone ethyl ether ethylene acetal. 
     
     
       5. The process of claim 1, wherein the conversion percentage of said Birch's reduction is below 98.5%. 
     
     
       6. The process of claim 1, wherein the enamine formation reaction of said mixture of steroids is carried out in an alcohol solvent. 
     
     
       7. The process of claim 6, wherein said alcohol solvent is selected from the group consisting of methanol and ethanol. 
     
     
       8. The process of claim 1, wherein said secondary amine is pyrrolidine, piperidine, morpholine, or dimethylamine. 
     
     
       9. The process of claim 1, wherein the enamine formation reaction is carried out in an alcohol solvent and the extraction of the formed C 3  -enamine of 19-nor-Δ 4  -androstene-3,17-dione with an aqueous solution of an inorganic acid is effectuated by 1. evaporating the alcohol solvent,   2. adding a second solvent of benzene, toluene, chloroform, methylene chloride, dichloroethane, trichloroethane, diethyl ether or ethyl acetate, which is readily separable from water and which readily dissolves the alkyl or aralkyl ether of estrone in order to dissolve or suspend the reaction product of said enamine formation reaction,   3. extracting said C 3  -enamine dissolved or suspended in said second solvent with an aqueous solution of an inorganic acid, and then   4. extracting by-product steroids contained in the aqueous solution of the inorganic acid used for extraction of said C 3  -enamine with said second solvent.   
     
     
       10. The process of claim 1, wherein the pH of the aqueous solution of the inorganic acid is below 1. 
     
     
       11. The process of claim 1, wherein more than 1.5 equivalents of said inorganic acid per one equivalent of said secondary amine is used. 
     
     
       12. The process of claim 1, wherein the hydrolysis of said C 3  -enamine is effectuated by adding an alkali into said aqueous solution of the inorganic acid containing said extracted C 3  -enamine. 
     
     
       13. The process of claim 12, wherein said alkali is selected from the group consisting of sodium hydroxide and potassium hydroxide. 
     
     
       14. The process of claim 1, wherein said secondary amine which is used for the enamine formation reaction and is formed during the hydrolysis of said C 3  -enamine is removed by washing the solution which is obtained by extraction of the separated 19-nor-Δ 4  -androstene-3,17-dione with chloroform, benzene or ethy acetate which is readily separable from water and which readily dissolves 19-nor-Δ 4  -androstene-3,17-dione, with an aqueous acid solution. 
     
     
       15. In a process for separating 19-nor-Δ 4  -androstene-3,17-dione from a mixture of steroids which is obtained by the Birch's reduction with less than 98.5% conversion, of an alkyl or an aralkyl ether of estrone acetal having the following formula (I), ##SPC8## wherein R is selected from the group consisting of an alkyl group containing 1 to 10 carbon atoms and an aralkyl group containing a side chain of 1 to 5 carbon atoms; X and Y are selected from the group consisting of O-alkyl and S-alkyl groups, respectively, containing 1 to 10 carbon atoms; or the following formula (II), ##SPC9## wherein R is as defined above; Z and W are selected from the group consisting of oxygen atom and sulfur atom; and n represents an integer of from 2 to 10; followed by the hydrolysis of the obtained product of said Birch's reduction, the improvement which comprises   1. reacting said mixture of steroids containing 19-nor-Δ 4  -androstene-3,17-dione with a secondary amine in an alcohol solvent to form the C 3  -enamine of 19-nor-Δ 4  -androstene-3,17-dione,   2. evaporating the alcohol solvent,   3. adding a second solvent which is readily separable from water and which readily dissolves the alkyl or aralkyl ether of estrone, in order to dissolve or suspend the reaction product of said enamine formation reaction,   4. extracting said C 3  -enamine dissolved or suspended in said second solvent with an aqueous solution of an inorganic acid, the pH of which is below 1,   5. extracting by-product steroids contained in the aqueous solution of the inorganic acid used for extraction of said C 3  -enamine, with said second solvent,   6. hydrolyzing the separated C 3  -enamine of 19-nor-Δ 4  -androstene-3,17-dione by adding an alkali into said aqueous solution of the inorganic acid containing said extracted C 3  -enamine,   7. extracting 19-nor-Δ 4  -androstene-3,17-dione which is obtained by said hydrolysis of the C 3  -enamine of 19-nor-Δ 4  -androstene-3,17-dione, with an organic solvent which is readily separable from water and which readily dissolves 19-nor-Δ 4  -androstene-3,17-dione, and then,   8. removing said secondary amine which is used for the enamine formation reaction and which is formed during the hydrolysis of said C 3  -enamine by washing the solution which is obtained by extraction of the separated 19-nor-Δ 4  -androstene-3,17-dione with said organic solvent, with an aqueous acid solution.